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J. Biol. Chem., Vol. 281, Issue 21, 14632-14643, May 26, 2006

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Interleukin-1 Enhances GABA_A Receptor Cell-surface Expression by a Phosphatidylinositol 3-Kinase/Akt Pathway

RELEVANCE TO SEPSIS-ASSOCIATED ENCEPHALOPATHY^*

Rocío Serantes¹, Francisco Arnalich, María Figueroa, Marta Salinas^¶, Eva Andrés-Mateos², Rosa Codoceo, Jaime Renart^||, Carlos Matute^**, Carmen Cavada, Antonio Cuadrado^¶, and Carmen Montiel³

From the Departamento de Medicina, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Departamentos de Farmacología, ^¶Bioquímica, and Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, ^||Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid, and the ^**Departamento de Neurociencias, Facultad de Medicina, Universidad del País Vasco, Barrio de Sarriena, 48940 Leioa, Spain

Sepsis-associated encephalopathy (SAE) is a frequent but poorly understood neurological complication in sepsis that negatively influences survival. Here we present clinical and experimental evidence that this brain dysfunction may be related to altered neurotransmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher interleukin-1 (IL-1) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1 effect on type A -aminobutyric acid receptors (GABA_ARs), which mediate fast synaptic transmission in most cerebral inhibitory synapses in mammals, was investigated in cultured hippocampal neurons and in Xenopus oocytes expressing native or foreign rat brain GABA_ARs, respectively. Confocal images in both cell types revealed that IL-1 increases recruitment of GABA_ARs to the cell surface. Moreover, brief applications of IL-1 to voltage-clamped oocytes yielded a delayed potentiation of the GABA-elicited chloride currents (I_GABA); this effect was suppressed by IL-1ra, the natural IL-1 receptor (IL-1RI) antagonist. Western blot analysis combined with I_GABA recording and confocal images of GABA_A Rs in oocytes showed that IL-1 stimulates the IL-1RI-dependent phosphatidylinositol 3-kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of GABA_ARs into the cell surface. The interruption of this signaling pathway by specific phosphatidylinositol 3-kinase or Akt inhibitors suppresses the cytokine-mediated effects on GABA_AR, whereas activation of the conditionally active form of Akt1 (myr-Akt1.ER*) with 4-hydroxytamoxifen reproduces the effects. These findings point to a previously unrecognized signaling pathway that connects IL-1 with increased "GABAergic tone." We propose that through this mechanism IL-1 might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE.

Received for publication, November 22, 2005 , and in revised form, February 27, 2006.

^* This work was supported in part by Ministerio de Ciencia y Tecnología Grant SAF2005-00951, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo Grant PI021056, and Fundación Mutua Madrileña, Spain (to C. M. and F. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a fellowship from the Ministerio de Sanidad y Consumo, Spain.

² Recipient of a fellowship from the Universidad Autónoma de Madrid, Spain.

³ To whom correspondence should be addressed: Dept. de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain. Tel.: 34-91-4975390; Fax: 34-91-4975353; E-mail: carmen.montiel{at}uam.es.

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